Commentary on cancer research, information on supplements and treatments, relevant book reviews, links to useful sites and other information that cancer sufferers, their families and friends may find useful.

Pages

Monday, 26 November 2012

In the PINC - stopping the reverse Warburg Effect

There was an interesting report recently on some work in the US looking at the use of a common anti-malarial drug and
breast cancer. The drug in question is chloroquine, which is both cheap and
widely used throughout the world. Aside from its action against the parasite
that causes malaria, the drug is also known as an inhibitor of autophagy, which
is a cellular state in which the cell digests parts of itself, normally as a survival
mechanism in the face of lack of nutrients or damage to cell components.

The study in question is called the PINC
trial (Preventing Invasive Neoplasia with Chloroquine), which is specifically
looking at women with ductal carcinoma in situ (DCIS), which is a pre-cancerous
condition that is often picked up through breast screening. DCIS has the
potential to progress to fully blown breast cancer. Part of the problem of the
over-diagnosis of cancer associated with breast screening is that currently there
is no way to be sure which DCIS lumps are going to become life-threatening
cancer and which will remain harmless. The PINC trial is about treating women
with DCIS who are waiting for surgery with chloroquine for four weeks and then
to assess the effect this has on the DCIS lump. More details on the trial are
available here: http://clinicaltrials.gov/ct2/show/NCT01023477

While the trial has yet to report it’s
findings, the initial signs are looking positive. If chloroquine can stop DCIS
lesions from developing into invasive cancers that would be a major step
forward for women. Stopping cancer before it develops is a much better strategy
than simply turning every woman with a DCIS lesion into a cancer patient
because you don’t know how the lesion is going to develop.Why should stopping autophagy halt the
development of cancer? One explanation lies in the theories being developed by
Michael Lisanti and his co-workers (which I have covered here and here).
In a fundamental reworking of accepted theories of tumour metabolism and cancer
progression, Dr Lisanti and his group have shown that tumour cells act on the
tumour microenvironment to push the cells surrounding the tumour to switch to a
different metabolic pathway, and that these cells generate high-energy
by-products which the tumour cells feed on to grow and multiply. This is the
opposite of the currently accepted theory (called the Warburg effect), in which
it is tumour cells that engage in this alternative metabolic pathway, in
contrast to normal cells. In effect the tumour cells enter into a parasitic
relationship with the non-cancer cells around them.

This new theory, called “two compartment
tumour metabolism”, describes the complex sequence of events that lead to this
metabolic coupling between cancer cells and the cells in the stroma around the
tumour. And this is where we find the link between the PINC trial and Dr
Lisanti’s work. Autophagy is how the cells around the tumour respond to the
highly inflammatory environment that the tumour cells create. Interrupt this
process and you can break the metabolic shuttling of nutrients from the
surrounding tissues to the tumour. This is what the “two compartment tumour
metabolism” theory predicts, and this is, hopefully, what is being shown to
happen in the PINC trial.

Stopping autophagy is one avenue of
approach, but the theory also suggests that stopping the tumour cells creating
the inflammatory environment around then can stop the surrounding cells from
being cannibalised by the tumour. And this is an avenue of approach that is
going to be explored by some of Dr Lisanti’s key collaborators,
here in the UK.

This new work will also focus on women with DCIS waiting for surgery.
Instead of chloroquine, the women will take a range of anti-oxidants
that will counter the inflammation produced by the cells in the DCIS
lesions. If the anti-oxidants stop the cells surrounding the DCIS lumps
from switching metabolic pathway it should stop the parasitic
relationship forming and therefore the DCIS cells will not have the fuel
they need to progress and become invasive cancer cells.